BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers.

Abstract

Topoisomerase I (TOP1) inhibitors trap TOP1 cleavage complexes resulting in DNA double-strand breaks (DSBs) during replication, which are repaired by homologous recombination (HR). Triple-negative breast cancer (TNBC) could be eligible for TOP1 inhibitors given the considerable proportion of tumors with a defect in HR-mediated repair (BRCAness). The TOP1 inhibitor irinotecan was tested in 40 patient-derived xenografts (PDXs) of TNBC. BRCAness was determined with a single-nucleotide polymorphism (SNP) assay, and expression of Schlafen family member 11 (SLFN11) and retinoblastoma transcriptional corepressor 1 (RB1) was evaluated by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry analyses. In addition, the combination of irinotecan and the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor VE-822 was tested in SLFN11-negative PDXs, and two clinical non-camptothecin TOP1 inhibitors (LMP400 and LMP776) were tested. Thirty-eight percent of the TNBC models responded to irinotecan. BRCAness combined with high SLFN11 expression and RB1 loss identified highly sensitive tumors, consistent with the notion that deficiencies in cell cycle checkpoints and DNA repair result in high sensitivity to TOP1 inhibitors. Treatment by the ATR inhibitor VE-822 increased sensitivity to irinotecan in SLFN11-negative PDXs and abolished irinotecan-induced phosphorylation of checkpoint kinase 1 (CHK1). LMP400 (indotecan) and LMP776 (indimitecan) showed high antitumor activity in BRCA1-mutated or BRCAness-positive PDXs. Last, low SLFN11 expression was associated with poor survival in 250 patients with TNBC treated with anthracycline-based chemotherapy. In conclusion, a substantial proportion of TNBC respond to irinotecan. BRCAness, high SLFN11 expression, and RB1 loss are highly predictive of response to irinotecan and the clinical indenoisoquinoline TOP1 inhibitors.

• Authors: Florence Coussy, Rania El-Botty, Sophie Château-Joubert, Ahmed Dahmani, Elodie Montaudon, Sophie Leboucher, Ludivine Morisset, Pierre Painsec, Laura Sourd, Léa Huguet, Fariba Nemati, Jean-Luc Servely, Thibaut Larcher, Sophie Vacher, Adrien Briaux, Cécile Reyes, Philippe La Rosa, Georges Lucotte, Tatiana Popova, Pierre Foidart, Nor Eddine Sounni, Agnès Noel, Didier Decaudin, Laetitia Fuhrmann, Anne Salomon, Fabien Reyal, Christopher Mueller, Petra Ter Brugge, Jos Jonkers, Marie-France Poupon, Marc-Henri Stern, Ivan Bièche, Yves Pommier, Elisabetta Marangoni
• Journal: Science translational medicine (Sci Transl Med) Vol. 12 Issue 531 (02 19 2020) ISSN: 1946-6242 [Electronic] United States
• PMID: 32075943 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Nuclear Proteins
• RB1 protein, human
• Retinoblastoma Binding Proteins
• SLFN11 protein, human
• Topoisomerase I Inhibitors
• Irinotecan
• Ubiquitin-Protein Ligases

Topics

• Humans
• Irinotecan (pharmacology, therapeutic use)
• Nuclear Proteins (metabolism)
• Retinoblastoma Binding Proteins
• Topoisomerase I Inhibitors (pharmacology, therapeutic use)
• Triple Negative Breast Neoplasms (drug therapy, genetics)
• Ubiquitin-Protein Ligases